Genetic screening for inherited diseases based on the use of specific gene probes is a promising technology that will augment both the breadth and the precision of genetic diagnostic testing. There are an estimated 3,000 genetic disorders known which result from a single gene mutation, for which the application of specific gene probes is of direct value. In addition, however, there are a number of common disorders, such as rheumatoid arthritis (RA) and type I diabetes (or insulin-dependent diabetes mellitus, IDDM, hereinafter "diabetes"), which result not from a single gene mutation but from a combination of genetic and possibly environmental factors. In such cases, genetic inheritance determines the predisposition, or disease risk, associated with a large proportion of clinical disease. Thus, genetic testing for diabetes should be viewed as the identification of genetic predisposition, distinct from the more conventional notion of a single gene defect resulting in a specific inherited disease.
The identification of a particular gene associated with predisposition to diabetes can be viewed from two different perspectives. On the one hand, the gene being detected may be linked on the chromosome to other genes which actually confer disease susceptibility, in which case the gene being tested would function as a marker gene. On the other hand, the gene being identified may itself contribute directly to disease, but only if other genetic elements or appropriate environmental agents are present. Both of these concepts are important for understanding the genetic predisposition to diabetes.
The major genetic contribution to both diabetes and rheumatoid arthritis is encoded in a portion of chromosome 6 known as the major histocompatibility complex. Within this gene complex, a series of 14 linked genes constitutes the HLA class II gene cluster. Products of these class II genes are essential in the normal immune response for the triggering of the activation steps which lead to immunity. Even when the immune system is activated inappropriately, and attacks normal tissue, causing autoimmunity, these class II molecules play an essential role in the immune activation which leads to disease. This has led to the concept that the role of the HLA class II genes in autoimmune diseases such as type I diabetes is to function as a permissive molecular signal, like a "green light" which signals the immune system to proceed with an attack on a particular target. In type I diabetes, the target is assumed to be cellular components associated with the insulin-secreting cells of the pancreas. Thus, in many respects, the question of genetic predisposition in diabetes is an issue of identifying which HLA class II genes are responsible for aberrant signals in the activation of the autoimmune response.
The association of HLA class II genes with diabetes and with rheumatoid arthritis has been suspected for some time. The products of HLA genes carry the HLA typing specificities, which are conventionally measured using serologic reactivities. These typing specificities are a partial measure of genetic polymorphisms within the HLA gene complex. One of these serologic polymorphisms, known as HLA DR4, is present in approximately 70-75% of patients with either type I diabetes or classic rheumatoid arthritis. The utility of this serologic marker for disease predisposition analysis is hampered, however, by the fact that approximately 35% of the normal population also type as HLA DR4.